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Background: Both hyperoxemia and hypoxemia are deleterious in critically ill patients. Targeted oxygenation is recommended to prevent both of these extremes, however this has not translated to the bedside. Hyperoxemia likely persists more than hypoxemia due to absence of immediate discernible adverse effects, cognitive biases and delay in prioritization of titration., Methods: We present the methodology for the Titration Of Oxygen Levels (TOOL) trial, an open label, randomized controlled trial of an algorithm-based FiO 2 titration with electronic medical record-based automated alerts. We hypothesize that the study intervention will achieve targeted oxygenation by curbing episodes of hyperoxemia while preventing hypoxemia. In the intervention arm, electronic alerts will be used to titrate FiO 2 if SpO 2 is ≥94% with FiO 2 levels ≥0.4 over 45 min. FiO 2 will be titrated per standard practice in the control arm. This study is being carried out with deferred consent. The sample size to determine efficacy is 316 subjects, randomized in a 1:1 ratio to the intervention vs. control arm. The primary outcome is proportion of time during mechanical ventilation spent with FiO 2  ≥ 0.4 and SpO 2  ≥ 94%. We will also assess proportion of time during mechanical ventilation spent with SpO 2  < 88%, duration of mechanical ventilation, length of ICU and hospital stay, hospital mortality, and adherence to electronic alerts as secondary outcomes., Conclusion: This study is designed to evaluate the efficacy of a high fidelity, bioinformatics-based, electronic medical record derived electronic alert system to improve targeted oxygenation in mechanically ventilated patients by reducing excessive FiO 2 exposure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Hypogammaglobulinemia (serum IgG levels < 7.0 g/L) has been associated with increased risk of COPD exacerbations but has not yet been shown to predict hospitalizations., Research Question: To determine the relationship between hypogammaglobulinemia and the risk of hospitalization in patients with COPD., Study Design and Methods: Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status., Results: The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P < .001); pooled SHR (meta-analysis) was 1.29 (95% CI, 1.06-1.56, P = .01). Among patients with prior COPD admissions (n = 757), the pooled SHR increased to 1.58 (95% CI, 1.20-2.07, P < .01). The risk of COPD admissions, however, was similar between IgG groups in patients with no prior hospitalizations: pooled SHR = 1.15 (95% CI, 0.86-1.52, P =.34). The hypogammaglobulinemia group also showed significantly higher rates of COPD hospitalizations per person-year: 0.48 ± 2.01 vs 0.29 ± 0.83, P < .001., Interpretation: Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Although inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear., Research Question: Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes?, Study Design and Methods: We conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site., Results: The trial enrolled 738 patients (73.4% men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95% CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (incidence rate ratio, 1.64; 95% CI, 1.01-2.66)., Interpretation: Among patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies., (Copyright © 2020 American College of Chest Physicians. All rights reserved.)

Background: The National Emphysema Treatment Trial (NETT) showed a clear survival and quality of life benefit for patients selected for lung volume reduction surgery (LVRS). However, long-term outcomes after LVRS are still lacking. The aim of this study was to evaluate overall mortality and functional durability in this single-institution cohort of patients undergoing LVRS., Methods: A single-institution registry identified all patients who had undergone LVRS from January 2006 through August 2017. Records were retrospectively reviewed, and data were collected to include pulmonary functions test values, he University of California, San Diego shortness of breath questionnaire and complication and mortality rate., Results: LVRS was performed in 135 patients with a 2.2% 90-day mortality rate (n = 3). Estimated 1-, 2- and 5-year survival was 0.94 (95% confidence interval [CI], 0.88 to 0.97), 0.91 (95% CI, 0.83 to 0.95), and 0.71 (95% CI, 0.57 to 0.81), respectively. Mean improvement in forced expiratory volume in 1 second% predicted from preoperative baseline at 1 and 2 years was 5.3 (95% CI, 3.1 to 7.4) and 4.3 (95% CI, 1.9 to 6.6), respectively. There was a mean improvement in maximum workload of 5.2 W (95% CI, 0.9 to 9.4) at 1 year. Also, shortness of breath questionnaire scores had a mean decrease of -17.3 points (95% CI, -21.8 to -13) at 6 months and -13.9 points (95% CI, -18.4 to -9.3) at 1 year., Conclusions: LVRS is an effective operation with overall improvement in functional status and quality of life in appropriately selected patients., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Rationale: Characteristics associated with adherence to long-term oxygen therapy (LTOT) in COPD remain unclear., Objectives: To identify patient characteristics at the time of oxygen initiation associated with its adherence., Methods: We conducted a secondary analysis of data from 359 COPD participants assigned to oxygen in the Long-term Oxygen Treatment Trial. Participants were prescribed continuous (n = 214) or intermittent (n = 145) oxygen based on desaturation patterns at study entry. At the time of initial prescription, participants rated their perceived readiness, confidence, and importance to use oxygen on a 0-10 scale (0 = not at all, 10 = very much). During follow-up, they self-reported average hours per day of use (adherence). Adherence was averaged over short-term (0-30 days), medium-term (months 9-12), and long-term (month 13 to last follow-up) intervals. Multivariable logistic regression models explored characteristics associated with high adherence (≥16 h/day [continuous] or ≥8 h/day [intermittent]) during each time interval., Results: Participant readiness, confidence, and importance at the time of oxygen initiation were associated with high short- and medium-term adherence. For each unit increase in baseline readiness, the odds of high short-term adherence increased by 21% (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.05-1.40) and 94% (OR 1.94, 95% CI 1.45-2.59) in the continuous and intermittent groups, respectively. In both groups, high adherence in the medium-term was associated with high adherence in the long-term (continuous, OR 12.49, 95% CI 4.90-31.79; intermittent, OR 38.08, 95% CI 6.96-208.20)., Conclusions: Readiness, confidence, and importance to use LTOT at initiation, and early high adherence, are significantly associated with long-term oxygen adherence., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To evaluate whether asthma and airway hyper-responsiveness are associated with HIV infection., Methods: We reviewed the literature on HIV-associated pulmonary diseases, pulmonary symptoms, and immune changes which may play a role in asthma. The information was analyzed comparing the pre-HAART era to the post-HAART era data., Results: HIV-seropositive individuals commonly experience respiratory complaints yet it is unclear if the frequency of these complaints have changed with the initiation of HAART. Changes in pulmonary function testing and serum IgE are seen with HIV infection even in the post-HAART era. An increased prevalence of asthma among HIV-seropositive children treated with HAART has been reported., Conclusion: The spectrum of HIV-associated pulmonary disease has changed with the introduction of HAART. Current data is limited to determine if asthma and airway hyper-responsiveness are more common among HIV-seropositive individuals treated with HAART., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Plasma viral load and blood CD4 counts are accepted indicators of severity of illness in patients with HIV-1. Lung CD4 counts have not been evaluated in asymptomatic HIV-1 patients as indicators of disease severity., Objective: To determine if lung lymphocyte counts in asymptomatic subjects with HIV compare with plasma viral loads and blood CD4 counts in predicting survival., Design: Retrospective, cross-sectional analysis., Setting: Midwestern urban community, December 1996 to August 1998., Participants: HIV-seropositive subjects (n = 95) without AIDS-related pulmonary complications., Measurements: Plasma viral load, blood hemoglobin and blood lymphocyte subtypes, lung lymphocyte subtypes from BAL, body mass index, and mortality., Results: Eight of the 95 subjects (8.4%) had died at the 4-year follow-up. Lung CD4 counts were significantly related to mortality by univariable analysis (2.5 x 10(3)/mL vs 0.9 x 10(3)/mL, median values for survivors vs nonsurvivors, respectively, p = 0.010). Modeling using exact methods further showed lung CD4 counts to be a significant predictor of survival after individually adjusting for potential confounders, including plasma viral load and blood CD4 count., Conclusions: Lung CD4 counts in patients with HIV-1 infection may provide an independent predictor of survival.

Study Objectives: The goal of this study was to evaluate the neuropsychological and psychological functioning of emphysema patients following lung volume reduction surgery (LVRS) compared with patients receiving only medical therapy (MT)., Design: Patients with moderate-to-severe emphysema who were enrolled in the National Emphysema Treatment Trial at two sites (National Jewish Medical and Research Center and Ohio State University) were given a neuropsychological battery at baseline, 6 to 10 weeks later (following participation in pulmonary rehabilitation), and at 6 months following randomization to either LVRS or MT treatment., Subjects and Measurements: Twenty patients randomized to MT, 19 patients randomized to LVRS, and 39 matched, healthy control subjects completed a battery of tests that measured cognitive functioning, depression, anxiety, and quality of life (QoL)., Results: Controlling for practice, patients in the LVRS treatment arm at the 6-month follow-up demonstrated significant improvement compared with MT patients in cognitive tasks involving sequential skills and verbal memory. The LVRS patients also showed significant reductions in depression compared with the MT patients, as well as improved physical and psychosocial QoL. Correlational analysis indicated that improved immediate verbal memory in the LVRS group was related to improved QoL. No associations were found between changes in cognitive function and changes in depression, exercise performance, or pulmonary functioning., Conclusion: Patients who received LVRS demonstrated improvement in specific neuropsychological functions, depression, anxiety, and QoL scores compared with patients with continued MT treatment 6 months following randomization. However, mechanisms for these neurobehavioral changes are unclear. Improved verbal memory and sequential skills following LVRS were not directly associated with depression or exercise capacity. Nonetheless, LVRS led to a strong and likely clinically significant improvement in neuropsychological functioning over and above that explained by practice effects or MT. This finding adds to the growing list of clinical benefits of LVRS over MT, and supports additional research into the underlying mechanisms of this therapeutic effect.

Study Objectives: Evidence exists that HIV-seropositive individuals may be at increased risk for the development of precocious pulmonary emphysema. HIV infection is also associated with antioxidant deficiency in both the serum and lungs, and it is therefore possible that increased oxidant stress may contribute to parenchymal lung injury occurring in the setting of HIV. We sought to determine the regional distribution of emphysema and regional distribution of glutathione (GSH) concentrations among HIV-seropositive subjects with emphysema., Design: Cross-sectional evaluation of a prospective, longitudinal study., Setting: University teaching hospital. SUBJECTS/MEASUREMENTS: HIV-seropositive subjects without AIDS-related pulmonary complications participating in a descriptive study of lung biology in HIV-seropositive individuals. Emphysema scoring and evaluation of emphysema lobar distribution was performed among 40 subjects with emphysema. Eleven subjects underwent BAL of the right middle lobe (RML) and right upper lobe (RUL) with measurement of epithelial lining fluid (ELF) GSH in each lobe., Results: We found that the mean emphysema scores were much higher in the upper lobes compared to the rest of the lung. Mean GSH levels were significantly greater in the RUL compared to the RML. The regional differences were present in both smokers and nonsmokers., Conclusions: We conclude that in the setting of HIV, emphysema is more prominent and lung GSH concentrations are higher in the upper lobes. We hypothesize that the increased GSH may represent a compensatory response to increased oxidant stress in the upper lobes.

Study Objectives: Recent evidence suggests that chronic or latent viral infection may be an important predisposing factor in the development of COPD among smokers. As such, understanding if HIV-seropositive smokers are at heightened risk for respiratory symptoms may have relevance with regard to COPD pathogenesis. The current study was done to systematically identify the prevalence of respiratory symptoms among an HIV-seropositive population and to identify associated clinical features., Design and Setting: Cross-sectional analysis at an academic medical center., Participants: Three hundred twenty-seven HIV-seropositive individuals without a history of AIDS-related pulmonary complications. Fifty-two HIV-negative individuals with a similar age and smoking history served as a comparison group., Measurements: Administration of the American Thoracic Society Division of Lung Diseases respiratory questionnaire, and pulmonary function studies., Results: Respiratory symptoms including dyspnea (41.6% vs 7.7%), cough (40% vs 25%), and phlegm production (41.9% vs 23.1%) were extremely common in the HIV-group and significantly more common than in the HIV-negative group. Current or prior cigarette smoking was the most important predictor of respiratory symptoms among the HIV-seropositive group. The use of the antiretroviral agent lamivudine was associated with a significant reduction in dyspnea., Conclusion: HIV-seropositive individuals are at increased risk for the development of respiratory symptoms even prior to the onset of AIDS-related pulmonary complications. This may reflect a heightened susceptibility to the effects of cigarette smoking.

Objective: The National Emphysema Treatment Trial (NETT) is a randomized, multicenter, clinical trial comparing two different methods of lung volume reduction surgery plus medical therapy to medical treatment alone in patients with advanced emphysema. The purpose of this article was to use the data obtained from the NETT to assess the ability of the single-breath diffusing capacity of the lung for carbon monoxide (DLCO) to predict the need for supplemental oxygen during rest and exercise, as well as overall exercise capacity., Methods: One thousand seventy-one patients with a mean (+/- SD) FEV(1) of 0.76 +/- 0.24 L were studied., Results: The mean DLCO was 8.0 +/- 3.1 mL/min/mm Hg (28 +/- 10% of predicted). The mean resting PaO(2) was 64 +/- 10 mm Hg. There was a positive association between DLCO and both resting PaO(2) and the requirement for oxygen during a walk at 1 mile per hour (mph). The odds of requiring supplemental oxygen while walking at 1 mph was nine times greater in patients with a DLCO of < or = 20% of predicted than for patients with a DLCO of > 35% of predicted, after adjusting for age and gender. Eighty four percent of individuals with a DLCO of < or = 20% required supplemental oxygen with low levels of exercise compared to 38% of those with a DLCO of > 35%., Conclusion: Our results demonstrated that patients with reduced DLCO, particularly when < or = 20% of predicted, are more likely to have reduced PaO(2) at rest and are more likely to require supplemental oxygen with low levels of activity. Thus, DLCO is useful in evaluating whether supplemental oxygen is required for exercise.